Faculty Bibliography

Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions.

Gyrification of the cortical mantle is a dynamic process that increases with cortical surface area and decreases with age. Increased gyrification is associated with higher scores on cognitive tasks in adults; however, the degree to which this relationship is independent of cortical surface area remains undefined. This study investigates whether regional variation in gyrification is associated with domain-general and domain-specific cognition. Our hypothesis is that increased local gyrification confers a functional advantage that is independent of surface area. To quantify regional gyrification, we computed the local gyrification index (LGI) at each vertex and averaged across a bilateral parietal-frontal region associated with general intelligence and reasoning (Jung and Haier 2007). A sample of 48 healthy adults (24 males/24 females; ages 18-68 years) completed a high-resolution 3 T T1-weighted MRI and standardized administration of the Wechsler Adult Intelligence Scale (WAIS). We found a positive correlation between cortical gyrification and working memory, which remained significant after controlling for cortical surface area. Results suggest that a higher degree of local cortical folding confers a functional advantage that is independent from surface area and evident for more dynamic or "fluid" cognitive processes (i.e., working memory) rather than over-learned or "crystallized" cognitive processes.

Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled "Cannabinoids and Epilepsy".

Malformations of cortical development are associated with epilepsy and cognitive dysfunction, and can occur in patients withSCN1Aion channel mutations. We report a novel and subtle bandlike subcortical heterotopia on integrated positron emission tomography-magnetic resonance imaging ( PET-MRI) in a patient with treatment-resistant epilepsy due to a de novoKCNQ1frameshift mutation. Our case highlights the potential for other channel mutations to cause both epilepsy and cortical malformations. Further scrutiny of high contrast resolution MRI studies is warranted for patients withKCNQ1and other epilepsy genes to further define their extended phenotype.

Purpose: Evaluate efficacy of add-on CBD for the treatment of seizures associated with LGS. Method: Eligible patients were 2-55 years old with a clinical diagnosis of LGS, >=8 drop seizures during 4-week baseline, and documented failure of >=1 antiepileptic drug (AED). Patients were randomised (1:1:1) to 20 mg/kg/day CBD, 10 mg/kg/day CBD, or placebo for 14 weeks (2-week titration; 12-week maintenance). The primary efficacy endpoint was percentage change from baseline in drop seizures/month over the 14-week treatment period for CBD vs. placebo; >=50% responder rate and percentage change in total seizures were assessed. Results: 225 patients were randomised (76 CBD 20 mg/kg, 73 CBD 10 mg/kg, 76 placebo); 9 CBD 20 mg/kg, 2 CBD 10 mg/kg, and 2 placebo patients withdrew. Groups were similar at baseline; mean age was 16 years (30% of patients >=18 years) and median drop seizures/month was 85 (IQR: 44, 168). Patients had failed a median of 6 and were taking a median of 3 AEDs. Reduction in drop seizures was significantly greater for CBD 20 mg/kg (42%) and CBD 10 mg/kg (37%) than placebo (17%; p = 0.0047 and p = 0.0016), as were >=50% responder rates (40% and 36% vs. 15%; p = 0.0006 and p = 0.0030) and reductions in total seizures (38% and 36% vs. 18%; p = 0.0091 and p = 0.0015). Adverse events (AEs) occurred in 94% of CBD 20 mg/kg, 84% of CBD 10 mg/kg, and 72% of placebo patients, and were mostly mild or moderate; the most common were somnolence and decreased appetite. Treatment-related serious AEs occurred in 5 CBD 20 mg/kg, 2 CBD 10 mg/kg, and 0 placebo patients. Some elevations in transaminases were seen. There were no deaths. Of 212 completers, 99% entered the open-label extension study. Conclusion: Results suggest that add-on CBD for treatment of seizures associated with LGS may be efficacious, with more adverse events than placebo, but generally well-tolerated

Purpose: Assess the effect of CBD added to antiepileptic drug (AED) therapy for the treatment of drug-resistant seizures in Dravet syndrome. Method: This double-blind, placebo-controlled trial randomised 120 children aged 2-18 years with Dravet syndrome and drug-resistant seizures to receive CBD oral solution 20 mg/kg/day (n = 61) or placebo (n = 59) for 14 weeks (2 week titration; 12 week maintenance). The primary endpoint was the percentage change from baseline in convulsive seizures (tonic-clonic, tonic, clonic, and atonic) frequency over the 14-week treatment period. Results: The groups were well-balanced at baseline for demographics. Mean age was 10 years, with 29% of patients <6 years. Patients had previously tried a median 4 AEDs, and were currently taking a median 3 AEDs. Convulsive seizure frequency per month decreased from a median of 12.4 to 5.9 (median reduction of 39%) with CBD vs. 14.9 to 14.1 (median reduction of 13%) with placebo (difference between groups of 23%; p = 0.012). The proportion of patients with >=50% reduction in convulsive seizure frequency was 42.6% with CBD vs. 27.1% with placebo (OR=2.0; p = 0.078). Adverse events (AEs) occurred in 93.4% of CBD and 74.6% of placebo patients, and were mostly mild or moderate; the most common were somnolence, diarrhea, and decreased appetite. Serious AEs were reported in 16.4% of CBD and 5.1% of placebo patients, and were considered treatment-related in 8.2% of CBD patients, all of whom discontinued CBD. Some elevations in transaminases were noted without elevations of bilirubin; all were on concomitant valproate and all resolved. There were no deaths in the study. Conclusion: Results from this study suggest that CBD add-on therapy for drug-resistant seizures in Dravet syndrome may be efficacious, with more AEs than placebo but generally well tolerated